Association of accompanying dyspnoea with diagnosis and outcome of patients presenting with acute chest discomfort

Abstract Aims The presence of accompanying dyspnoea is routinely assessed and common in patients presenting with acute chest pain/discomfort to the emergency department (ED). We aimed to assess the association of accompanying dyspnoea with differential diagnoses, diagnostic work-up, and outcome. Methods and results We enrolled patients presenting to the ED with chest pain/discomfort. Final diagnoses were adjudicated by independent cardiologists using all information including cardiac imaging. The primary diagnostic endpoint was the final diagnosis. The secondary diagnostic endpoint was the performance of high-sensitivity cardiac troponin (hs-cTn) and the European Society of Cardiology (ESC) 0/1h-algorithms for the diagnosis of myocardial infarction (MI). The prognostic endpoints were cardiovascular and all-cause mortality at two years. Among 6045 patients, 2892/6045 (48%) had accompanying dyspnoea. The prevalence of acute coronary syndrome (ACS) in patients with vs. without dyspnoea was comparable (MI 22.4% vs. 21.9%, P = 0.60, unstable angina 8.7% vs. 7.9%, P = 0.29). In contrast, patients with dyspnoea more often had cardiac, non-coronary disease (15.3% vs. 10.2%, P < 0.001). Diagnostic accuracy of hs-cTnT/I concentrations was not affected by the presence of dyspnoea (area under the curve 0.89–0.91 in both groups), and the safety of the ESC 0/1h-algorithms was maintained with negative predictive values >99.4%. Accompanying dyspnoea was an independent predictor for cardiovascular and all-cause death at two years [hazard ratio 1.813 (95% confidence intervals, 1.453–2.261, P < 0.01)]. Conclusion Accompanying dyspnoea was not associated with a higher prevalence of ACS but with cardiac, non-coronary disease. While the safety of the diagnostic work-up was not affected, accompanying dyspnoea was an independent predictor for cardiovascular and all-cause death. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT00470587, number NCT00470587


Introduction
Acute myocardial infarction (AMI) remains the leading cause of premature death worldwide. [1][2][3] Each year, about 15 million patients present to the emergency department (ED) with acute chest pain/discomfort, the cardinal symptom of AMI. [1][2][3] Rapid identification of AMI as a life-threatening cause of acute chest pain/discomfort is crucial for the early initiation of highly effective evidence-based therapy. Electrocardiography (ECG) and cardiac troponin (cTn) form the diagnostic cornerstones and complement clinical assessment in the ED. 1,[3][4][5][6][7][8][9][10][11] A relevant proportion of patients presenting to the ED with acute chest pain/discomfort do also complain about dyspnoea. Unfortunately, the impact of accompanying dyspnoea on the prevalence of AMI, the differential diagnosis, the diagnostic accuracy of hs-cTnT/I concentrations, and the hs-cTnT/I-based rapid algorithms, as well as the short-and long-term outcomes of these patients is largely unknown. Pilot studies, most of which had limited granularity in patient phenotyping and exclusively investigated dyspnoea as an alternative to chest pain/discomfort as the presenting symptom, but did not evaluated dyspnoea as an accompanying symptom, suggested that the presence of dyspnoea may impact on the final diagnosis and may be associated with worse outcome. [12][13][14][15][16][17][18] To address this major gap in knowledge, we addressed these research questions within a large international multicentre diagnostic study that prospectively assessed the presence of accompanying dyspnoea in patients presenting with acute chest pain/discomfort to the ED.

Study design and population
This was a secondary analysis from a prospective international multicentre study including 12 centres in five countries aiming at advancing the early diagnosis of AMI (NCT00470587). [19][20][21][22][23] The study was carried out according to the principles of the Declaration of Helsinki and approved by the local ethics committees. Haemodynamically stable adult patients presenting to the ED with acute chest pain/discomfort and able and willing to provide written informed consent were recruited. While enrolment was independent of renal function, patients with terminal kidney failure on chronic dialysis were excluded.
For this analysis, patients with missing data on the presence of accompanying dyspnoea, and those with an unknown diagnosis after final adjudication and at least one elevated hs-cTnT concentration possibly indicating AMI, were excluded. For the secondary analysis including the diagnostic performance of high-sensitivity cardiac troponin (hs-cTn) and the European Society of Cardiology (ESC) 0/1h-algorithms, patients with ST-segment elevation myocardial infarction (STEMI) and those with missing blood samples or hs-cTnT and hs-cTnI measurements at 1 h were excluded. The most common reasons for missing samples after 1 h were early transfer to the catheter laboratory or coronary care unit and diagnostic procedures that precluded blood draws around the 1 h window. The authors designed the study, gathered, and analysed the data according to the STrengthening the Reporting of OBservational studies in Epidemiology guidelines 24 for observational studies in epidemiology (see Supplementary material online, Table S1), vouched for the data and analysis, wrote the paper, and decided to submit it for publication.

Assessment of accompanying dyspnoea
Study staff, mostly physicians, prospectively and systematically evaluated the presence or absence of dyspnoea as an additional symptom accompanying acute chest pain/discomfort as a binary variable (yes/no) and documented on a standardized study-specific case report form while assessing the patient in the ED. 21,22,[25][26][27][28]

Centrally adjudicated final diagnosis
Two independent cardiologists performed the central adjudication of the final diagnosis applying current guidelines 3 and the universal definition of myocardial infarction (MI) 29 using two sets of data: first, all available medical records obtained during clinical care including history, physical examination, and results of laboratory testing including serial clinical (hs)-cTn levels, radiologic testing, ECG, echocardiography, cardiac exercise test, lesion severity and morphology in coronary angiography, and cardiac magnetic resonance imaging-pertaining to the patient from the time of ED presentation to 90-day follow-up; and second, study-specific assessments including detailed chest pain characteristics using 34 predefined criteria, serial hs-cTnT blood concentrations obtained from study samples, and clinical follow-up by telephone and/or mail. In situations of disagreement about the diagnosis, cases were reviewed and adjudicated in conjunction with a third cardiologist.

Follow-up and clinical endpoints
Patients were contacted at 3, 12, and 24 months after discharge by telephone calls or in written form. We obtained information regarding death during follow-up from the patient's hospital records, the family physician's records and the national death registry. The primary diagnostic endpoint was the association of accompanying dyspnoea with final adjudicated diagnoses of patients. The second diagnostic endpoint was the performance of hs-cTn and the ESC 0/1h-algorithms in patients with vs. without dyspnoea quantified by the safety for rule-out, accuracy for rule-in, and overall efficacy. The primary prognostic endpoint was two-year all-cause mortality.

Statistical analysis
Final differential diagnoses of patients with vs. without accompanying dyspnoea are depicted in bar charts. We constructed boxplots to assess and visualize differences in hs-cTnT and hs-cTnI concentrations at presentation between patients with vs. without accompanying dyspnoea in patients with non-ST-segment elevation myocardial infarction (NSTEMI) compared to patients with other final diagnoses. We further constructed receiver-operating-characteristics (ROC) curves and calculated corresponding areas under the curve (AUC) to assess the discriminative performance of hs-cTnT and hs-cTnI concentrations at presentation to diagnose NSTEMI in patients with vs. without accompanying dyspnoea. We also assessed the AUC for the clinical judgment of the likelihood for an acute coronary syndrome (ACS) as assessed by the treating physician in the ED based on the clinical examination, the ECG, and the first clinical (hs)-cTn measurement. AUCs of independent ROC curves were compared as recommended by Hanley et al. 30 The diagnostic performance of the ESC 0/1h-algorithms was assessed by safety for rule-out [quantified by the resulting sensitivity and negative predictive value (NPV)], accuracy for rule-in [quantified by the resulting specificity and positive predictive value (PPV)], and overall efficacy (quantified by the percentage of patients triaged either towards rule-out or rule-in). We used cross tables derived by the application of the recommended assay-specific cut-off criteria for rule-out or rule-in of MI to calculate diagnostic performance parameters and 95% confidence intervals (95%CI) using the Wilson score method without continuity correction. Specificity, PPV, sensitivity, and NPV between independent groups were compared using Fisher's exact test. We performed a univariable and multivariable cox proportional hazard model including common confounders which are available at presentation of patients to the ED. We calculated crude as well as adjusted hazard ratios (HRs) and created a forest plot to assess the prediction of accompanying dyspnoea of twoyear cardiovascular and all-cause mortality. Cumulative all-cause mortality during two years of follow-up according to presence or absence of accompanying dyspnoea was plotted in Kaplan-Meier curves, and the log-rank test was used to assess differences in survival between groups. Continuous variables are described as median with interquartile range (IQR) and categorical variables by numbers and percentages. Continuous variables were compared with the Mann-Whitney U test, and categorical variables using the Pearson X 2 test or Fisher's exact test, as appropriate.
All hypothesis testing was two-tailed, and P values of less than 0.05 were considered to indicate statistical significance without adjustments for multiple testing. Statistical analyses were performed using SPSS for Mac, version 28.0 (SPSS Inc., Chicago, IL, USA) and R version 4.1.2 (Vienna, Austria).

Study cohort and characteristics of patients
From April 2006 to April 2018, 6684 patients were prospectively enrolled. Overall, 100 patients had missing information on accompanying dyspnoea. 6045 patients were eligible for the primary analysis, 4734 patients for the secondary analysis using the ESC hs-cTnT 0/1h-algorithm, and 4586 patients for the secondary analysis using the ESC hs-cTnI 0/ 1h-algorithm (see Supplementary material online, Figure S1). Patients with accompanying dyspnoea were older, more often female, and more often had known cardiovascular risk factors and known coronary artery disease ( Table 1). Baseline characteristics of patients that were excluded due to missing information on dyspnoea overall were comparable to those patients in the final analysis (see Supplementary material online, Table S2).

Association of accompanying dyspnoea with differential diagnoses
Overall, differential diagnoses among patients with vs. without accompanying dyspnoea differed (P < 0.001). While the prevalence of   NSTEMI including type 1 MI and type 2 MI subtypes as well as UA were comparable, cardiac, non-coronary disease was more common (15.3% vs. 10.2%), and non-cardiac disease (50.5% vs. 57.2%) less common in patients with accompanying dyspnoea vs. those without ( Figure 1A). Among those with cardiac non-coronary disease, patients with accompanying dyspnoea had a much higher prevalence of adjudicated heart failure (30% vs. 7.8%, P < 0.001, Figure 1B). Patients with non-cardiac conditions and accompanying dyspnoea more often had pulmonary disease such as pneumonia and chronic obstructive pulmonary disease and less often musculoskeletal chest pain ( Figure 1C).

Cox proportional hazards regression analysis
In univariable cox regression analyses, accompanying dyspnoea was associated with cardiovascular and all-cause mortality at two years [unadjusted HRs 2.243 (1.703-2.954) and 2.487 (95%CI, 2.001-3.091), respectively, both P < 0.001]. In multivariable cox regression models, after adjustment for other significant predictors of outcome including cardiovascular risk factors as well as confounders that are available at presentation, accompanying dyspnoea remained an independent predictor for cardiovascular and all-cause mortality at two years of followup [adjusted HRs 1.576 (95%CI, 1.193-2.083) and 1.813 (95%CI, 1.453-2.261), respectively, both P < 0.01; Table 2, Figure 4].

Discussion
We assessed the impact of accompanying dyspnoea on final diagnoses, on diagnostic performance of hs-cTn and the ESC 0/1h-algorithms, and on the outcome of patients presenting with acute chest pain/discomfort to the ED. We report six major findings: first, chest pain/discomfort patients with accompanying dyspnoea were slightly older, more often female, and more often had arterial hypertension and diabetes. Second, accompanying dyspnoea was not associated with a higher ACS prevalence. However, patients with dyspnoea more often had Impact of accompanying dyspnoea in patients with acute chest discomfort cardiac, non-coronary (15.3% vs. 10.1%), and less often non-cardiac disease (50.5% vs. 57.2%). Third, hs-cTnT and hs-cTnI concentrations at presentation were similar in patients with NSTEMI irrespective of the presence of accompanying dyspnoea. In contrast, patients with other final diagnoses than NSTEMI and accompanying dyspnoea had slightly (10-20%) higher hs-cTnT and hs-cTnI concentrations than those without dyspnoea. This difference may be explained by the fact that patients with accompanying dyspnoea more often had cardiac, non-coronary disease, such as heart failure, which often is associated with acute and chronic myocardial injury. Furthermore, both BNP and NT-proBNP concentrations at presentation were higher in patients with vs. without accompanying dyspnoea, reflecting underlying cardiac disease and increased intracardiac filling pressures. Fourth, while overall the diagnostic accuracy of hs-cTnT/I concentrations for NSTEMI and the early clinical judgment for the presence of an ACS were very high also in patients with accompanying dyspnoea (AUC 0.89 for hs-cTnT, 0.90 for hs-cTnI, and 0.85 for clinical judgment, respectively), these patients stayed slightly longer in the ED and were much more likely to require hospitalisation (41% vs. 32%) vs. patients without accompanying dyspnoea. Fifth, while the high safety of the ESC 0/1h-algorithms was maintained in patients with accompanying dyspnoea with very high NPV and sensitivity, the specificity and PPV for rule-in slightly decreased in patients with dyspnoea [specificity 95.2% (95%CI, 94.1-96.1) vs. 97.7% (95%CI, 96.9-98.2), P < 0.001; PPV 79.4% (95%CI, 75.4-83.0) vs. 86.6% (95%CI, 82.6-89.8), P = 0.01]. The presence of dyspnoea affected the overall performance of the ESC 0/1h-algorithms as fewer patients were triaged towards rule-out and slightly more patients towards rule-in. Consequently, more patients remained in the observe zone. As dyspnoea was associated with higher hs-cTn concentrations due to other underlying cardiac disease than MI, these findings are well in line with previous studies investigating the performance of the ESC 0/ 1h-algorithms in the elderly and those with renal dysfunction. 21,31,32 Sixth, after adjustment for other significant predictors of outcome, dyspnoea remained an independent predictor for cardiovascular and all- tients with and (B) patients without accompanying dyspnoea. *, if chest pain onset >3 h; Delta, unsigned change within the first hour; NSTEMI, non-ST-segment elevation myocardial infarction; Sens., sensitivity; NPV, negative predictive value; Prev., prevalence; Spec., specificity; PPV, positive predictive value; hs-cTnT, high-sensitivity cardiac troponin T. (C+D) Diagnostic performance of the ESC hs-cTnI 0/1h-algorithm. Diagnostic performance of the ESC hs-cTnI 0/1h-algorithm in (C) patients with and (D) patients without accompanying dyspnoea. *, if chest pain onset >3 h; Delta, unsigned change within the first hour; NSTEMI, non-ST-segment elevation myocardial infarction; Sens., sensitivity; NPV, negative predictive value; Prev., prevalence; Spec., specificity; PPV, positive predictive value; hs-cTnI, high-sensitivity cardiac troponin I. cause mortality at two years of follow-up with HRs of 1.576 (95%CI, 1.193-2.083) and 1.813 (1.453-2.261, both P < 0.01), respectively. Furthermore, patients with accompanying dyspnoea were at much higher risk for cardiovascular and all-cause mortality at two years.
These findings confirm and extend prior work in which dyspnoea was assessed as an alternative symptom to chest pain/discomfort. 33,34 Among 592 dyspnoeic patients presenting to the ED, clinical uncertainty, as assessed by the treating ED physician, was present in 185 (31%) patients, with a low diagnostic accuracy of clinical judgment (AUC 0.76, 95%CI, 0.69-0.83) for the presence of acute heart failure. Clinical uncertainty was an independent predictor of death. 34 In a secondary analysis from the multicentre randomized controlled PROMOTION (Patient Response tO Myocardial Infarction fOllowing a Teaching Intervention Offered by Nurses) trial, differences in symptoms leading to ED presentations among 3522 patients with known CAD were investigated. 17 At two years of follow-up, 234 patients presented with non-ACS vs. 331 patients with ACS. Dyspnoea was present in 33% vs. 25% (P = 0.028), respectively, and therefore more prevalent in patients with non-ACS. Also in the prehospital setting, dyspnoea was found to be predominantly present in elderly female patients and associated with significantly increased mortality rates compared to patients presenting with chest pain [13% (IQR 12-15) vs. 2.9% (2.6-3.2) at 30 days and 50% (IQR 47-54) vs. 20% (IQR 19-21) at 4 years]. 35 In a large series of patients referred for myocardial-perfusion single-photon-emission computed tomography, self-reported dyspnoea identified a subgroup of otherwise asymptomatic patients at increased risk for death from cardiac or any cause irrespective of the presence of known CAD. Since the authors only coded dyspnoea among patients without chest pain, they could not evaluate the potential interaction between dyspnoea and symptoms of chest pain. Although we have investigated the impact of dyspnoea in a different clinical setting, most of our findings are well in line with those reported with a nearly identical HR for all-cause death at 2 years. 33 Our results indicate that accompanying dyspnoea in chest pain/discomfort patients is an important symptom and imply that when dyspnoea is present, the risk of death from any cause is increased. Accordingly, it seems appropriate to include an evaluation of dyspnoea in the clinical assessment of patients presenting with chest pain/discomfort to the ED and to evaluate whether a further diagnostic work-up is indicated to identify and potentially treat the underlying cause, such as heart failure, pulmonary embolism, or COPD.
Our findings do also extend data previously obtained for the diagnostic performance of the ESC 0/1h-algorithm assessed in all-comers with acute chest discomfort. 7,8,10,36 The safety of the ESC 0/1h-algorithms remained very high in patients with accompanying dyspnoea.  However, one has to consider that the overall performance was slightly impaired in patients with dyspnoea due to the higher prevalence of chronic and acute myocardial injury, similarly to patients with kidney failure or the elderly, resulting in lower PPV for rule-in and a higher number of patients remaining in the observe zone. 21,31,32 Some limitations merit consideration when interpreting these findings. First, our study was conducted in ED patients with symptoms suggestive of MI. Further studies are required to quantify the impact of accompanying dyspnoea in chest pain patients with a higher pre-test probability (e.g. in a coronary care unit setting) or in patients with a lower pre-test probability (e.g. in a general practitioner setting) for MI. Second, no specific sample size calculation was performed. Although this secondary analysis from an ongoing multicentre study is one of the largest ever performed, it still may have been underpowered for some comparisons. Third, not all patients with acute chest pain had a second set of laboratory measurements at 1 h. The most common reasons for missing blood samples were logistic issues in the ED that precluded blood draw around the 1 h window. However, it is unlikely that the absence of these patients significantly influenced our results. Fourth, although we used the most stringent methodology to adjudicate the presence or absence of MI including central adjudication by experienced cardiologists and serial measurements of hs-cTn, we still may have misclassified a small number of patients. Fifth, as the presence of dyspnoea was self-reported, we cannot exclude that the prevalence of underlying conditions might be slightly under-or overestimated. Sixth, BNP and NT-proBNP concentrations at presentation were only available in a subset of patients. Furthermore, we did not systematically assess left and right ventricular function and intracardiac pressures to answer the question whether heart failure might have been the major driver of higher mortality rates in patients with dyspnoea. Finally, we cannot generalize our findings to patients with terminal kidney failure requiring dialysis, since they were excluded from this study.

Conclusion
Accompanying dyspnoea was not associated with a higher prevalence of ACS but with cardiac, non-coronary disease. While the safety of the diagnostic work-up was not affected, accompanying dyspnoea was an independent predictor for cardiovascular and all-cause death.

Supplementary material
Supplementary material is available at European Heart Journal: Acute Cardiovascular Care online.

Funding
This work was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the University of Basel, the University Hospital Basel, Abbott, Beckman Coulter, Biomerieux, Idorsia, Ortho Cinical Diagnostics, Quidel, Roche, Siemens, and Singulex.

Conflict of interest:
The authors designed the study, gathered and analysed the data, vouched for the data and analysis, wrote the paper, and decided to publish. J.B., T.N., L.K., P.L.-A., M.R.G., K.W., and C.M. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and approved the manuscript. The sponsors had no role in designing or conducting the study and no role in gathering or analysing the data or writing the manuscript. The manuscript and its contents have not been published previously and are not being considered for publications elsewhere in whole or in part in any language, including publicly accessible websites or e-print servers. We disclose that J.B. received research grants from the University of Basel, the University Hospital of Basel, the Division of Internal Medicine, the Swiss Academy of Medical Sciences, the